3-123814362-G-C

Variant names:

• chr3-123814362-G-C
• rs10934651
• NM_053025.4:c.-4+17186C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_053025.4(MYLK):​c.-4+17186C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0911 in 152,140 control chromosomes in the GnomAD database, including 1,027 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.091 (1027 hom., cov: 32)
• Consequence: MYLK NM_053025.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.371
• Publications: 1 publications found

Genes affected

MYLK (HGNC:7590): (myosin light chain kinase) This gene, a muscle member of the immunoglobulin gene superfamily, encodes myosin light chain kinase which is a calcium/calmodulin dependent enzyme. This kinase phosphorylates myosin regulatory light chains to facilitate myosin interaction with actin filaments to produce contractile activity. This gene encodes both smooth muscle and nonmuscle isoforms. In addition, using a separate promoter in an intron in the 3' region, it encodes telokin, a small protein identical in sequence to the C-terminus of myosin light chain kinase, that is independently expressed in smooth muscle and functions to stabilize unphosphorylated myosin filaments. A pseudogene is located on the p arm of chromosome 3. Four transcript variants that produce four isoforms of the calcium/calmodulin dependent enzyme have been identified as well as two transcripts that produce two isoforms of telokin. Additional variants have been identified but lack full length transcripts. [provided by RefSeq, Jul 2008]

MYLK Gene-Disease associations (from GenCC):

• aortic aneurysm, familial thoracic 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
• megacystis-microcolon-intestinal hypoperistalsis syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: G2P
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• megacystis-microcolon-intestinal hypoperistalsis syndrome

  Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics

ENSG00000207002 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4	c.-4+17186C>G		intron_variant	Intron 3 of 33	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8	c.-4+17186C>G		intron_variant	Intron 3 of 33	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes AF: 0.0911 AC: 13851 AN: 152020 Hom.: 1025 Cov.: 32

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0917

Gnomad ASJ AF: 0.0628

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0557

Gnomad OTH AF: 0.0958

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0911 AC: 13859 AN: 152140 Hom.: 1027 Cov.: 32 AF XY: 0.0994 AC XY: 7395 AN XY: 74374

African (AFR) AF: 0.0882 AC: 3663 AN: 41520

American (AMR) AF: 0.0914 AC: 1398 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 218 AN: 3470

East Asian (EAS) AF: 0.398 AC: 2053 AN: 5158

South Asian (SAS) AF: 0.216 AC: 1039 AN: 4802

European-Finnish (FIN) AF: 0.133 AC: 1411 AN: 10576

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0557 AC: 3786 AN: 68002

Other (OTH) AF: 0.100 AC: 211 AN: 2110

Alfa AF: 0.0302 Hom.: 22

Bravo AF: 0.0877

Asia WGS AF: 0.304 AC: 1055 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.46
DANN	Benign	0.67
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10934651; hg19: chr3-123533209;